Vaccine-induced CD8+ T cells eliminate tumors by a two-staged attack

Abstract

Data presented here demonstrate that vaccine-induced CD8 þ T cells can eliminate their specific tumor-target with a two-staged attack. First, they release interferon-g that results in growth arrest of the tumor cells via induction of antiangiogenic mediators. Then, during the latter stages of the immune response, CD8 þ effector T cells eradicate the remaining tumor cells through perforinmediated lysis. A combination of these two mechanisms is highly effective in the described model, while either pathway alone fails to completely achieve tumor rejection. needed activation signals to the innate and adaptive immune system, and vaccine-induced TAAspecific CD8 þ T cells have been shown to achieve tumor rejection. 3,4 The success or failure of immune surveillance against any rapidly proliferating threat is a predicament of numbers versus time. Tumor cells grow very rapidly and can thus hold out against immune surveillance. CD8 þ Tcell-mediated lysis, the ultimate weapon to specifically eliminate transformed cells, is inefficient and time consuming, 5 potentially allowing continued expansion of a tumor even in the presence of a vigorous cytolytic T-cell response. A similar predicament is faced by antiviral CD8 þ T cells that face an even more rapidly multiplying threat. In viral systems, exemplified by a mouse model of hepatitis B virus, CD8 þ T cells can control the infection not only by lysis of virus-infected cells, but also through the release of mediators that reduced production of viral proteins, 6 required for the assembly of infectious virus.Here we demonstrate that vaccine-induced TAAspecific CD8 þ T cells can resort to a similar pathway by eliminating their specific tumor target with a twostaged attack. The model is based on an E1-deleted adenoviral vector expressing the E7 of HPV-16 (termed AdHu5E7) shown previously to induce a potent transgene product-specific CD8 þ T-cell response. 7 AdHu5E7-induced CD8 þ T cells are able to protect mice against challenge with a syngeneic tumor cell line, 4 termed TC-1, expressing the E7 and E6 oncoproteins of human papillomavirus (HPV) type-16. 8 In order to trace the vaccine-induced T cells within regressing tumors, the TC-1 cells were mixed with an extract of growth factor-reduced basement membranes called matrigel, 9 a substance that has been used extensively to study tumor angiogenesis, 10 tumor progression and cancer therapies. 11,7 Using this model, our data indicate that vaccine-induced E7-specific CD8 þ T cells invade the tumor where they initially release interferon (IFN)-g that affects growth arrest of the tumor cells. This is at least in part achieved through induction of factors, such as MIG, known to inhibit angiogeneisis, 12 which in turn is essential to permit proliferation of transformed cells within a solid tumor. At a later stage, CD8 þ effector T cells eliminate the tumor cells through cytolysis. A combination of these two mechanisms is highly effective in this experimental model, while either pathway alone ultimately fails to inhibit tumor progression....

The role of CD95 and CD95 ligand in cancer

“…14 Likely, the most established proapoptotic activity of CD95 is to mediate the apoptotic death of either virus-infected or cancer cells when engaged by a CD8+ cytotoxic lymphocyte (CTL; Figure 1). In addition to the perforin/granzyme pathway 15 and some indirect mechanisms involving cytokines such as tumor necrosis factor- α (TNF α) and interferon- γ , 16, 17, 18, 19, 20, 21, 22, 23 CD95/CD95L is a direct major system that both CTLs as well as CD4+ cytolytic effector T cells use to eliminate neoplastically transformed cells. 24, 25, 26, 27, 28, 29 CD95 can also mediate receptor interacting protein (RIP)-1-dependent necroptosis under circumstances of caspase inhibition or knockdown of TRAF2.…”

Solid tumors “melt” from the inside after successful CD8 T cell attack

“…IFN-c secreted by tumor-specific T cells has been demonstrated to inhibit blood vessel formation in growing tumors [19,20,24,34,35], either directly [39] or by inducing IP-10 [40] or Mig [41], factors that are known to inhibit angiogenesis. The present study extends these findings by demonstrating that the adoptive transfer of P14 T cells leads to destruction of the vasculature of established GP33-expresssing tumors.…”

“…Second, IFN-c produced at the tumor site can trigger production of additional inflammatory cytokines and chemokines that subsequently lead to activation and recruitment of NK cells, macrophages or granulocytes [30,31]. Third, IFNc may render tumor stroma that is essential for tumor growth vulnerable to attack by many cells of the immune system [23] and fourth, IFN-c can inhibit tumor angiogenesis [19,20,24,[32][33][34][35].…”

Dice

“…47 In a lung cancer mouse model, Lewis lung cancer cells were rejected in vivo in a manner dependent on CD8+ T cells that killed cancer cells independently of perforin or CD95L. 48 Depending on the tumor models studied, antitumor activity was found to depend on IFNγ, 49,50 IFNγ and CD95L, 51 first IFNγ then Pfp in a 2-hit model, 52 IFNγ and TNFα, 53 or TNFα. 54 One study suggested that neither Pfp nor CD95 nor TNFα were involved.…”